A facile synthesis of (S)-felodipine

Article abstract of DOI:10.1016/j.tet.2011.10.025

A short and facile synthesis of (S)-felodipine was developed starting from (R)-glycidol as the source of the chiral auxiliary. 2-Hydroxyethyl esters were found to undergo selective transesterification reactions in the presence of other esters. This selective transesterification reaction was applied to the synthesis of (S)-felodipine through selective substitution of the 2-hydroxyethyl group possessing chiral ester with sodium methoxide.

Full text of DOI:10.1016/j.tet.2011.10.025

Tetrahedron 67 (2011) 10222e10228
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A facile synthesis of (S)-felodipine
*
Kuktae Kwon, Jung A. Shin, Hee-Yoon Lee
Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and facile synthesis of (S)-felodipine was developed starting from (R)-glycidol as the source of the
chiral auxiliary. 2-Hydroxyethyl esters were found to undergo selective transesterification reactions in
the presence of other esters. This selective transesterification reaction was applied to the synthesis of
(S)-felodipine through selective substitution of the 2-hydroxyethyl group possessing chiral ester with
sodium methoxide.
Received 22 September 2011
Received in revised form 8 October 2011
Accepted 10 October 2011
Available online 19 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydropyridine
Resolution
Transesterification
Hantzsch
Chemoselective
1. Introduction
1,4-Dihydropyridines are involved in a plethora of biological
activities in addition to the redox system in nature as NADH co-
enzymes and their analogs. These various biological activities led
1,4-dihydropyridines being used in the treatment of vascular dis-
orders, cancer, diabetes, AIDS and many other diseases.1
1,4-Dihydropyridines have been readily available through the
Hantzsch condensation reaction that was first reported in 1882.2 As
a result, many effective drugs known as calcium channel blockers
with 1,4-dihydropyridine core structure have been developed for
the treatment of high blood pressure (Fig. 1).3
Many of these 1,4-dihydropyridine calcium channel blockers
exist as mixtures of enantiomers. Apparently, enantiomers of these
1,4-dihydropyridines show different pharmacological effects
ranging from moderate difference in pharmacokinetics to complete
change of biological activities.4 Thus, the development of these
drugs as single enantiomeric forms would provide a significant
improvement in pharmacological effects.5 However, most 1,4-
dihydropyridine calcium channel blockers have been developed
as racemic drugs. It is only recent that amlodipine, the leading
calcium channel blocker, was developed as a single enantiomeric
form.6 For the preparation of single enantiomeric 1,4-
dihydropyridines, there have been only a few reports of asym-
metric synthesis using organocatalysts7 or chiral auxiliaries8 with
limited asymmetric induction. Most of the reports for the
* Corresponding author. Tel.: þ82 42 250 2835; fax: þ82 42 250 2810; e-mail
address: leehy@kaist.ac.kr (H.-Y. Lee).
Fig. 1. Dihydropyridine calcium channel blockers.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.025

K. Kwon et al. / Tetrahedron 67 (2011) 10222e10228
10223
preparation of single enantiomers utilized chiral resolution
through separation of diastereomers with chiral auxiliaries4c,9 or
diastereomeric salts,6,10 or through enzymatic separation.11 A pro-
cess for chiral amlodipine was developed using the chiral resolu-
tion of two enantiomers through diastereomeric salt formation.6
In 1989, Lamm reported a preparation of (S)-felodipine, that is,
the more potent drug than the (R)-isomer, using (R)-3-
chloropropane-1,2-diol as the starting material for the chiral aux-
iliary.9 Diastereomers of the 1,4-dihydropyridine obtained through
Hantzsch reaction were separated and were converted into enan-
tiomerically pure felodipines. Lamm was able to determine the
absolute stereochemistry of the more potent isomer as the (S)-
isomer. We became interested in developing a practical route to (S)-
felodipine and decided to modify Lamm’s synthetic route in a hope
to convert both diastereomeric 1,4-dihydropyridines obtained from
Hantzsch reaction into (S)-felodipine as shown in the Scheme 1.
sulfone 3 and will be converted to (S)-felodipine. The isomer 20 with
(S)-configuration could undergo transesterification reaction12 to 4
with a hope that the ethyl ester will react faster than the other ester
of secondary alcohol. After switching to the methyl ester, 4 will be
converted into (S)-felodipine through oxidation to sulfone followed
by the selective hydrolysis and ethyl ester formation. This synthetic
strategy would be a highly efficient one since it does not waste
undesired isomer separated through chiral resolution. Herein we
report a discovery of hydroxyl group accelerated selective trans-
esterification reaction and its application to the synthesis of (S)-
felodipine, which was developed into a process for a large scale
preparation of (S)-felodipine.13
2. Result and discussion
The synthesis of (S)-felodipine started with (R)-glycidol by
protecting the free alcohol as the THP ether (Scheme 2). The choice
of (R)-glycidol was purely random as either enantiomer would form
the same diastereomeric mixture only with mirror images. Though
THP ether produced diastereomeric mixture in 1, the sensitivity of
glycidol under basic reaction conditions that were required for the
introduction of many other protecting groups made the THP group
as the preferred protecting group especially for a large scale re-
action. Next, the epoxide was treated with the thiophenoxide anion
to produce the secondary alcohol 1. With the chiral auxiliary 1 in
hand, synthesis of 1,4-dihydropyridine was accomplished in three
step sequence. Esterification of 1 with diketene produced 5 and it
was converted into 6 through Knoevenagel reaction with 2,3-
dichlorobenzaldehyde. After the Hantzsch ester synthesis from 6
and ethyl 3-aminocrotonate, the THP protecting group was re-
moved from the 1,4-dihydropyridine to produce diastereomeric
products 2 and 20. At this stage, since the desired isomer 2 would be
converted into the corresponding sulfone that was known to pro-
duce (S)-felodipine through eliminative hydrolysis of the chiral
auxiliary followed by esterification reaction, feasibility of the se-
lective transesterification reaction of the undesired isomer 20 was
examined.
The transesterification reaction by NaOMe was tested using
varying amount of NaOMe, concentration, and reaction time (Table
1). To our surprise, completely unexpected selectivity of the
transesterification reaction was observed. In all cases, trans-
esterification reaction proceeded faster at the ester of the chiral
auxiliary. When 3 equiv of NaOMe was used, equal mixture of
felodipine and dimethyl ester 9 was obtained with complete con-
version after 20 h (entry 1). When the reaction time was shortened
to 6 h, the conversion was still complete and the amount of 9 was
reduced substantially. When the amount of NaOMe was reduced,
the ratio of 8/9 improved further (entries 3 and 4). When the
concentration of the reaction was doubled to expedite the reaction,
conversion was complete in 5.5 h without the formation of 9 (entry
7). For comparison, when
7 was treated under the trans-
esterification reaction condition, no transesterification product was
observed (entry 8). This result indicated that the free hydroxyl
group of 2 not only facilitate the hydrolysis of the chiral ester but
also affected the transesterification reaction of the ethyl ester of 2.
To further confirm the role of the free hydroxyl group in the
transesterification reaction, a sterically hindered model substrate
10 was subjected to the transesterification reaction with NaOMe.
The transesterification reaction proceeded cleanly to produce the
corresponding methyl ester. When the free hydroxyl group of 10
was protected as THP ether, no transesterification reaction was
observed (Scheme 3).
Scheme 1. Synthetic plan of (S)-felodipine from glycidol.
Since the chiral auxiliary in Lamm’s synthesis could be prepared
from (R)-glycidol that has become commercially available in large
quantity, we believed that (R)-glycidol would allow this synthetic
route to be a practical one. Another modification would be the
deferment of the sulfide oxidation to sulfone with a plan to convert
both diastereomers obtained through Hantzsch reaction into (S)-
felodipine. The sulfonyl group that is used to discriminate two es-
ters of the dihydropyridine core would be introduced after the
separation of two diastereomeric sulfide intermediates 2 and 20.
The isomer 2 with desired (R)-configuration will be oxidized to the
These results clearly demonstrated that the free hydroxyl group
played an activating role in the transesterification reaction. It is
presumed that the alkoxide generated from the free hydroxyl group
coordinated to the ester carbonyl group intramolecularly to activate

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K. Kwon et al. / Tetrahedron 67 (2011) 10222e10228
Scheme 2. Preparation of the 1,4-dihydropyridine intermediates for (S)-felodipine.
Table 1
Selectivity and reactivity of the transesterification reaction
Scheme 4. Plausible activation pathway of the ester group.
1,4-dihydropyridine compounds. This reaction eliminated the re-
quirement of an electron-withdrawing group for the selective hy-
Entry
Substrate
Equiv/concn
Time (h)
Conversion (%)
8/9
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
7
3/0.2
3/0.2
20
6
16
9
8
6
100
100
100
100
100
100
100
0
1/1.7
1/0.4
1/0.2
1/0.1
1/0.3
1/0.2
1/0
drolysis and allowed exploration of
a possible asymmetric
induction during Hantzsch dihydropyridine synthesis using various
chiral auxiliaries. Substituting thiophenyl group with seemingly
bulkier groups, such as sulfone, tartrate or sulfonamide of aniline
for the Hantzsch reaction did not induce any diastereoselectivity
(Table 2). From the substituent similar in size (entry 1) to larger
1.1/0.2
1.1/0.2
1.1/0.4
1.1/0.4
1.1/0.4
3/0.2
5.5
20
d
Table 2
Chiral induction in Hantzsch reaction
Entry OR
OR0
Yielda (ratio) Yield (%)
1
54% (1/1)
52% (1/1)
80b
84
Scheme 3. Hydroxyl group promoted transesterification reaction.
2
the ester group that would react with methoxide or methanol faster
than the unactivated ester group (Scheme 4). A similar observation
was reported for the selective transesterification reaction of
b-
3
44% (1/1)
d
ketoesters presumably through
a same type of activation
mechanism.14
a
The selective transesterification reaction of 2-hydroxyethyl es-
ters changed the synthetic strategy of asymmetric synthesis of
Yield for Hantzsch reaction and deprotection.
b
Yield for transesterification reaction of the (R)-isomer.

K. Kwon et al. / Tetrahedron 67 (2011) 10222e10228
10225
substituents (entries 2 and 3), no bias was observed. Nevertheless,
in all cases except tartrate ester (entry 3), transesterification re-
action of the 2-hydroxyethyl esters, 14a and 14b produced felodi-
pine selectively. Inability of the selective transesterification
reaction with the tartrate ester also supports the mechanism in the
Scheme 4 as other coordination structures, which do not activate
the ester group are possible in 14c for the selective trans-
esterification reaction.
nuclear magnetic resonance spectroscopy (13C NMR) was recor-
ded on Brucker FT AM 300 (75 MHz) and Brucker FT AM 400
(100 MHz) and was fully decoupled by broad band decoupling.
Chemical shifts were reported in parts per million referenced to
the center line of a triplet at 77.0 ppm of chloroform-d. Mass
spectra were recorded on a VG AUTOSPEC Ultma GC/MS system
using direct insertion probe (DIP) and electron impact (EI)
(70 eV) method.
Since we have discovered that 2-hydroxyethyl esters undergo
transesterification reaction with NaOMe selectively, 2 was con-
verted into (S)-felodipine directly through the transesterification
reaction with NaOMe. Thus the synthetic steps of (S)-felodipine
from (R)-glycidol was shortened to seven step sequence.
4.1.1. 2-(Oxiran-2-ylmethoxy)-tetrahydro-2H-pyran. Pyridinium p-
toluenesulfonate (1.00 g, 4.05 mmol) and 3,4-dihydro-2H-pyran
(11.3 mL, 121.5 mmol) were added to a stirred solution of oxiran-
2-ylmethanol (6.00 g, 80.99 mmol) in dichloromethane (80 mL)
at 0 ꢀC under argon atmosphere. After 6 h, aqueous NaHCO3 so-
lution (60 mL) was added and the layers were separated. The
aqueous layer was extracted with dichloromethane (3ꢁ50 mL).
Combined organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture was purified by column
chromatography (EtOAc/hexane¼1/5). Product (9.22 g, 72%);
Isomer 1; 1H NMR (300 MHz, CDCl3) 4.54e4.51 (m, 2H),
4.03e4.01 (m, 1H), 3.05e3.03 (m, 2H), 2.68e2.65 (m, 2H),
2.54e2.51 (m, 1H), 1.51e1.48 (m, 2H), 1.45e1.39 (m, 4H); Isomer
2; 1H NMR (300 MHz, CDCl3) 4.54e4.51 (m, 2H), 3.99e3.97 (m,
1H), 3.05e3.03 (m, 2H), 2.68e2.65 (m, 2H), 2.48e2.46 (m, 1H),
1.51e1.48 (m, 2H), 1.45e1.39 (m, 4H).
3. Conclusion
We have discovered that esters containing 2-hydroxyethyl
groups undergo selective transesterification reaction in the pres-
ence of other alkyl esters. This selective transesterification reaction
was applied to the synthesis of (S)-felodipine starting from (R)-
glycidol in seven step sequence through resolution of two isomers
obtained via Hantzsch reaction. The selective transesterification
reaction eliminated the introduction of electron-withdrawing
group in the ester group and selective hydrolysiseesterification
steps. We are currently probing the activation mechanism, scope,
and limitation of the selective transesterification reaction of 2-
hydroxyethyl esters.
4.1.2. (2S)-1-(Phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-
2-ol (1). Benzenethiol (6.87 mL, 67.2 mmol) was added dropwise
to a suspension of sodium hydride (60% in mineral oil, 2.65 g,
67.2 mmol) in THF (50 mL) at 0 ꢀC under argon atmosphere. After
30 min, a solution of 2-(oxiran-2-ylmethoxy)-tetrahydro-2H-pyran
(9.22 g, 58.3 mmol) in THF (50 mL) was added to the reaction
mixture at 0 ꢀC and gradually warmed to room temperature. After
5 h, aqueous NH4Cl solution (30 mL) was added and the layers
were separated. Aqueous layer was extracted with EtOAc
(3ꢁ50 mL). Combined organic layer was dried over MgSO4, fil-
tered, and concentrated in vacuo. The crude mixture was purified
by column chromatography (EtOAc/hexane¼1/5). Product (14.23 g,
96%); Isomer 1; 1H NMR (300 MHz, CDCl3) 7.36e7.35 (d, J¼7.3 Hz,
2H), 7.26e7.21 (t, J¼7.8 Hz, 2H), 7.16e7.11 (t, J¼7.1 Hz, 1H),
4.52e4.51 (m, 1H), 3.85e3.78 (m, 2H), 3.67e3.62 (m, 2H),
3.5e3.48 (m, 1H), 3.38 (br s, 1H), 3.08e3.01 (m, 2H), 1.73e1.68 (m,
2H), 1.55e1.47 (m, 4H); Isomer 2; 1H NMR (300 MHz, CDCl3)
7.36e7.35 (d, J¼7.3 Hz, 2H), 7.26e7.21 (t, J¼7.8 Hz, 2H), 7.16e7.11 (t,
J¼7.1 Hz, 1H), 4.5e4.77 (m, 1H), 3.85e3.78 (m, 2H), 3.67e3.62 (m,
2H), 3.5e3.48 (m, 1H), 3.35 (br s, 1H), 3.08e3.01 (m, 2H), 1.73e1.68
(m, 2H), 1.55e1.47 (m, 4H).
4. Experimental
4.1. General methods
All oxygen or moisture sensitive reactions were carried out in
oven-dried glassware under the positive pressure of argon. Sensi-
tive liquids and solutions were transferred by syringe or cannula
and introduced through rubber septa through which a high flow of
argon was maintained. Unless otherwise stated, reactions were
carried out at room temperature.
Concentration of solution was accomplished by using a Buchi
rotary evaporator with an air pump. This was generally followed
by removal of residual solvents on a vacuum line held at
0.1e1 Torr. Unless otherwise stated, all commercial reagents and
solvents were used without additional purification. Chromatog-
raphy grade hexane and EtOAc were technical grade and
distilled before used. Et2O and THF were distilled from
sodiumebenzophenone ketyl under nitrogen. Triethylamine was
distilled from sodium. Dichloromethane and dimethylformamide
were distilled from P2O5. Benzene and toluene were washed with
concentrated sulfuric acid and water, and then dried over sodium
for more than 12 h before distillation. Concentration of alkyl
lithium solutions was determined by titration against diphenyl-
acetic acid. Analytical thin layer chromatography (TLC) was
performed on Merck precoated silica gel 60 F254 plates. Visuali-
zation on TLC was achieved by use of UV light (254 nm), expo-
sure to iodine vapor, or treatment with acidic anisaldehyde,
potassium permanganate, 5% phosphomolybdic acid in ethanol,
or ceric ammonium molybdate stain followed by heating. Flash
column chromatography was undertaken on silica gel (Merck 60,
230e400 mesh ASTM). Proton nuclear magnetic resonance
spectroscopy (1H NMR) was recorded on Bruker FT AM 300
(300 MHz) and Bruker FT AM 400 (400 MHz). Chemical shifts
were quoted in parts per million (ppm) referenced to the singlet
at 7.24 ppm for chloroform-d. The following abbreviations were
used to describe peak patterns when appropriate: br¼broad,
s¼singlet, d¼doublet, t¼triplet, q¼quadruplet, m¼multiplet.
Coupling constant, J was reported in Hertz unit (Hz). Carbon 13
4.1.3. (R)-1-(Phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-
2-yl 3-oxobutanoate (5). Pyridine (0.875 mL, 10.6 mmol) and
diketene (5.35 g, 63.62 mmol) were added to a stirred solution of
(2S)-1-(phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-2-
ol (14.23 g, 53.02 mmol) in acetone (106 mL) at room tempera-
ture and refluxed under argon atmosphere. After 4 h, the mixture
was cooled to room temperature and then water (50 mL) was
added to the reaction mixture and the layers were separated.
Aqueous layer was extracted with EtOAc (3ꢁ50 mL). Combined
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The crude mixture was purified by column chromatogra-
phy (EtOAc/hexane¼1/5). Product (13.81 g, 74%); Isomer 1; 1H
NMR (300 MHz, CDCl3) 7.39e7.34 (d, J¼7.2 Hz, 2H), 7.28e7.23 (t,
J¼8.3 Hz, 2H), 7.19e7.15 (t, J¼6.9 Hz, 1H), 5.16e5.13 (m, 1H),
4.57e4.56 (m, 1H), 3.90e3.88 (d, J¼4.7 Hz, 1H), 3.76e3.72 (m,
1H), 3.61e3.57 (m, 1H), 3.5e3.48 (m, 1H), 3.33e3.32 (d, J¼4.7 Hz,
2H), 3.2e3.15 (m, 2H), 2.21 (s, 3H), 1.7e1.62 (m, 2H), 1.56e1.22
(m, 4H); Isomer 2; 7.39e7.34 (d, J¼7.2 Hz, 2H), 7.28e7.23 (t,

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K. Kwon et al. / Tetrahedron 67 (2011) 10222e10228
J¼8.3 Hz, 2H), 7.19e7.15 (t, J¼6.9 Hz, 1H), 5.16e5.13 (m, 1H),
4.51e4.49 (m, 1H), 3.87e3.85 (d, J¼4.6 Hz, 1H), 3.76e3.72 (m, 1H).
3.61e3.57 (m, 1H), 3.5e3.48 (m, 1H), 3.33e3.32 (d, J¼4.7 Hz, 2H),
3.2e3.15 (m, 2H), 2.21 (s, 3H), 1.7e1.62 (m, 2H), 1.56e1.22 (m,
4H); 13C NMR (100 MHz, CDCl3) 200.1, 166.4, 135.4129.8, 129.0,
128.9, 128.9, 128.8, 126.5, 99.0, 98.5, 72.9, 72.6, 66.7, 66.4, 62.0,
61.9, 49.9, 34.2, 34.1, 30.3, 30.2, 30.0, 29.9, 25.2, 19.1, 19.0; High
resolution mass (ESI): calculated for C18H24O5S [MþNa]þ:
375.1242, found: 375.1251.
CDCl3) 167.4, 167.3, 166.4, 157.2, 147.9, 147.5, 144.0, 136.0, 132.8,
132.7, 130.2, 129.8, 129.6, 129.6, 129.1, 129.1, 128.8, 128.8, 128.2,
128.1, 128.1, 126.9, 126.8, 126.1, 125.9, 103.8, 103.5, 98.9, 98.8, 98.2,
71.0, 70.9, 70.5, 66.7, 61.6, 61.6, 59.7, 39.0, 38.7, 38.6, 30.3, 30.2,
25.3, 25.3, 19.9, 19.8, 19.5, 19.4, 19.1, 19.0, 14.2; High resolution
mass (ESI): calculated for C31H35Cl2NO6S [MþNa]þ: 642.1460,
found: 642.1461.
4.1.6. (R)-3-Ethyl 5-((S)-1-hydroxy-3-(phenylthio)propan-2-yl) 4-
(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (2). p-Toluenesulfonic acid monohydrate (395 mg,
2.075 mmol) was added to a stirred solution of 3-ethyl 5-(S)-1-
(phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl 4-(2,3-
dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox-
ylate (644 mg, 1.038 mmol) in ethanol (4 mL) at room temperature
under argon atmosphere. After 2 h, water (8 mL) was added and the
layers were separated. Aqueous layer was extracted with EtOAc
(3ꢁ5 mL). Combined organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The crude mixture was purified by
column chromatography (EtOAc/benzene¼1/2). Product (412 mg,
74%); 1H NMR (300 MHz, CDCl3) 7.36e7.33 (d, J¼7.6 Hz, 1H),
7.3e7.28 (m, 1H), 7.27e7.22 (m, 4H), 7.15e7.12 (m, 1H), 7.06e7.03
(m, 1H), 6.05 (s, 1H), 5.39 (s, 1H), 4.98e4.95 (m, 1H), 4.09e4.02 (m,
2H), 3.81e3.77 (m, 1H), 3.59e3.57 (m, 1H), 3.18e3.14 (m, 1H),
2.92e2.87 (m, 1H), 2.26e2.23 (d, J¼6.1 Hz, 6H), 1.2e1.13 (m, 3H);
13C NMR (100 MHz, CDCl3) 167.3, 166.7, 147.9, 146.2, 143.8, 135.4,
132.7, 130.6, 129.8, 129.5, 129.0, 128.8, 128.2, 127.0, 126.2, 103.2,
102.0, 77.3, 76.9, 76.6, 73.1, 63.1, 60.3, 59.7, 38.6, 34.0,19.6,19.2,14.2;
High resolution mass (ESI): calculated for C26H27Cl2NO5S [MþNa]þ:
558.0885, found: 558.0912.
4.1.4. (R)-1-(Phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-
2-yl 2-(2,3-dichlorobenzylidene)-3-oxobutanoate (6). 2,3-Dichlor-
obenzaldehyde (8.23 g, 47.02 mmol), piperidine (1.16 mL, 17.75
mmol), and acetic acid (1.02 mL, 17.75 mmol) were slowly added to
a stirred solution of (R)-1-(phenylthio)-3-(tetrahydro-2H-pyran-2-
yloxy)propan-2-yl 3-oxobutanoate (13.81 g, 39.18 mmol) in ben-
zene (80 mL) at room temperature under argon atmosphere. The
resulting mixture was refluxed and water was removed using
DeaneStark apparatus. After 2 h, mixture was cooled to room
temperature and then water (80 mL) was added and the layers
were separated. Aqueous layer was extracted with EtOAc
(3ꢁ50 mL). Combined organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The crude mixture was purified by
column chromatography (EtOAc/hexane¼1/5). Product (15.57 g,
78%); Isomer 1; 1H NMR (300 MHz, CDCl3) 7.81e7.79 (d, J¼7.8 Hz,
1H), 7.42e7.31 (m, 2H), 7.32e7.29 (d, J¼6.8 Hz, 1H), 7.27e7.24 (m,
3H), 7.19e7.15 (m, 2H), 5.32e5.27 (m, 1H), 4.54e4.51 (d, J¼11.4 Hz,
1H), 3.99e3.96 (m, 1H), 3.82e3.8 (m, 1H), 3.46e3.43 (m, 2H),
3.27e3.25 (m, 1H), 3.12e3.1 (m, 1H), 2.2 (s, 3H), 1.63e1.6 (m, 2H),
1.5e1.46 (m, 4H); Isomer 2; 1H NMR (300 MHz, CDCl3) 7.81e7.79 (d,
J¼7.8 Hz, 1H), 7.42e7.31 (m, 2H), 7.32e7.29 (d, J¼6.8 Hz, 1H),
7.27e7.24 (m, 3H), 7.19e7.15 (m, 2H), 5.22e5.15 (m, 1H), 4.45e4.42
(d, J¼11.3 Hz, 1H), 3.8e3.79 (m, 1H), 3.74e3.7 (m, 1H), 3.46e3.43
(m, 2H), 3.27e3.25 (m, 1H), 3.12e3.1 (m, 1H), 2.2 (s, 3H), 1.63e1.6
(m, 2H), 1.5e1.46 (m, 4H); 13C NMR (100 MHz, CDCl3) 200.9, 194.0,
194.0, 171.1, 165.9, 136.9, 135.3, 133.6, 131.6, 131.6, 131.6, 129.7, 129.7,
129.4, 129.3, 129.0, 129.0, 129.0, 129.0, 128.3, 127.8, 127.4, 127.4,
126.4, 98.8, 98.6, 73.4, 73.1, 66.3, 66.1, 62.0, 61.9, 60.3, 33.8, 31.5,
31.1, 30.2, 30.2, 27., 25.3, 25.2, 25.2, 25.2, 22.5, 20.9, 19.1, 19.0, 18.9,
14.1, 14.0; High resolution mass (ESI): calculated for C25H26Cl2O5S
[MþNa]þ: 531.0776, found: 531.0774.
4.1.7. (S)-3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (8). Sodium (5 mg, 0.2174 mmol)
was added to a methanol (0.5 mL) and stirred for 30 min. That NaOMe
solution in methanol (0.5 mL) was added to a neat (R)-3-ethyl 5-((S)-
1-hydroxy-3-(phenylthio)propan-2-yl) 4-(2,3-dichlorophenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (107 mg, 0.1995
mmol) and mixture was refluxed. After 5.5 h, solvent was removed
using evaporator, and aqueous ammonium chloride solution (10 mL)
was added. Aqueous layer was extracted with EtOAc (3ꢁ10 mL).
Combined organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo. The crude mixture was purified by column chroma-
tography (EtOAc/hexane¼1/2). (S)-Felodipine(64.4 mg, 84%);1H NMR
(300 MHz, CDCl3) 7.37e7.28 (m, 2H), 7.14e7.09 (t, J¼7.9 Hz, 1H), 5.87
(br s, 1H), 5.52 (s, 1H), 4.16e4.09 (q, J¼7.4 Hz, 2H), 3.66 (s, 3H),
2.39e2.35 (d, J¼3.1 Hz, 6H), 1.26e1.21 (t, J¼7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 167.8, 167.3, 148.1, 144.2, 144.2, 132.7, 130.9,
129.6, 128.1, 126.9, 103.8, 103.4, 59.8, 50.8, 38.5, 19.4, 19.4, 14.2; High
resolution mass (ESI): calculated for C18H19Cl2NO4 [MþNa]þ:
4.1.5. 3-Ethyl 5-(S)-1-(phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)
propan-2-yl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (7). Ethyl 3-aminocrotonate
(4.63 mL, 36.63 mmol) was added to a stirred solution of (R)-1-
(phenylthio)-3-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl 2-(2,3-
dichlorobenzylidene)-3-oxobutanoate (15.57 g, 30.56 mmol) in
pyridine (31 mL) and then refluxed. After 4 h, mixture was cooled
to room temperature and aqueous CuSO4 solution (50 mL) was
added and the layers were separated. Aqueous layer was extracted
with EtOAc (3ꢁ50 mL). Combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude mixture was
purified by column chromatography (EtOAc/hexane¼1/1). Product
(13.65 g, 72%); Isomer 1; 1H NMR (300 MHz, CDCl3) 7.36e7.26 (m,
2H), 7.23e7.2 (m, 4H), 7.18e7.12 (m, 1H), 7.06e7.03 (m, 1H), 5.68
(br s, 1H), 5.42 (s, 1H), 5.12e5.1 (m, 1H), 4.57e4.5 (m, 1H),
4.06e4.02 (q, J¼6.9 Hz, 2H), 3.76e3.67 (m, 2H), 3.42e3.4 (m, 2H),
3.2e3.16 (m, 1H), 3.01e2.97 (m, 1H), 2.26 (s, 6H), 1.6e1.49 (m, 2H),
1.55e1.43 (m, 4H) 1.18e1.13 (t, J¼3.1 Hz, 3H); Isomer 2; 1H NMR
(300 MHz, CDCl3) 7.36e7.26 (m, 2H), 7.23e7.2 (m, 4H), 7.18e7.12
(m, 1H), 7.06e7.03 (m, 1H), 5.64 (br s, 1H), 5.33e5.29 (d, J¼12.2 Hz,
1H), 5.12e5.1 (m, 1H), 4.4e4.1 (m, 1H), 4.06e4.02 (q, J¼6.9 Hz, 2H),
3.98e3.92 (m, 1H), 3.86e3.74 (m, 2H), 3.31e3.29 (m, 1H), 3.2e3.16
(m, 1H), 3.06e3.05 (m, 1H), 2.26 (s, 6H), 1.6e1.49 (m, 2H),
1.55e1.43 (m, 4H) 1.18e1.13 (t, J¼3.1 Hz, 3H); 13C NMR (100 MHz,
406.0589, found: 406.0583; ½a D24:5
ꢃ7.13 (c 1.0 in CH3OH, 589 nm)[lit.:
ꢂ
½
a 2D4:5
ꢂ
ꢃ7.3 (c 1.0 in CH3OH, 589 nm)].
4.1.8. (4R)-3-Ethyl 5-((2R)-1-(phenylsulfonyl)-3-(tetrahydro-2H-py-
ran-2-yloxy)propan-2-yl) 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (3). Oxone (196 mg, 0.318 mmol)
was added to a stirred solution of 3-ethyl 5-(S)-1-(phenylthio)-3-
(tetrahydro-2H-pyran-2-yloxy)propan-2-yl 4-(2,3-dichlorophenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (68 mg, 0.127
mmol) in DMF (5.0 mL) at room temperature under argon atmo-
sphere. After 12 h, NaHSO3 (250 mg) was added and stirred for
5 min. Water (5 mL) and saturated NaCl solution (2.5 mL) were
added and the layers were separated. Aqueous layer was extracted
with Et2O (20ꢁ3 mL). Combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAc/hexane¼2/1). Product
(52 mg, 72%); 1H NMR (300 MHz, CDCl3) 7.87e7.85 (d, J¼7.3 Hz, 2H),

K. Kwon et al. / Tetrahedron 67 (2011) 10222e10228
10227
7.57e7.52 (m, 1H), 7.51e7.46 (m, 2H), 7.26e7.2 (m, 2H), 7.09e7.05 (t,
J¼5.8 Hz, 1H), 6.06 (s, 1H), 5.34e5.32 (m, 1H), 4.82 (s, 1H), 4.07e4.02
(m, 2H), 3.71e3.65 (dd, J¼14.8 Hz, 8.4 Hz, 1H), 3.48e3.44 (dd,
J¼14.8 Hz, 3.3 Hz, 1H), 3.37e3.36 (m, 2H), 2.25e2.22 (d, J¼2.9 Hz,
6H), 1.54e1.52 (br s, 1H), 1.17e1.12 (m, 3H).
4.1.11. 3-(2R,3R)-1,4-Diethoxy-3-hydroxy-1,4-dioxobutan-2-yl 5-
ethyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (14c). Ethyl 3-aminocrotonate (0.062 mL, 0.486
mmol) was added to a stirred solution of (2R,3R)-diethyl 2-(2-(2,3-
dichlorobenzylidene)-3-oxobutanoyloxy)-3-(triisopropylsilyloxy)
succinate (266 mg, 0.4417 mmol) in pyridine (2 mL) and then
refluxed. After 6 h, mixture was cooled to room temperature and
aqueous CuSO4 solution (4 mL) was added and the layers were
separated. Aqueous layer was extracted with EtOAc (3ꢁ3 mL).
Combined organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo. The crude mixture was purified by column
chromatography (EtOAc/hexane¼1/2). Product (200 mg, 64%);
Isomer 1; 1H NMR (300 MHz, CDCl3) 7.30e7.28 (m, 1H), 7.27e7.15
(m, 1H), 7.01e6.98 (m, 1H), 6.28 (s, 1H), 5.535.52 (d, J¼2.8 Hz, 1H),
5.44 (s, 1H), 4.89e4.88 (m, 1H), 4.15e4.09 (m, 2H), 4.01e3.98 (m,
4H), 2.28 (s, 6H), 1.22e1.18 (m, 6H),1.16e1.14 (m, 3H), 1.00e0.82 (m,
2H); Isomer 2; 1H NMR (300 MHz, CDCl3) 7.30e7.28 (m, 1H),
7.27e7.15 (m, 1H), 7.01e6.98 (m, 1H), 6.21 (s, 1H), 5.49e5.48 (d,
J¼2.7 Hz, 1H), 5.53 (s, 1H), 4.89e4.88 (m, 1H), 4.01e3.98 (m, 1H),
3.80e3.77 (m, 2H), 2.22 (s, 6H), 1.22e1.18 (m, 6H), 1.16e1.44 (m,
3H), 1.00e0.82 (m, 2H).
1.0 M solution of tetrabutylammonium fluoride (1.0 mL) was
added to a stirred solution of 3-(2R,3R)-1,4-diethoxy-1,4-dioxo-3-
(triisopropylsilyloxy)butan-2-yl 5-ethyl 4-(2,3-dichlorophenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (150 mg, 0.21
mmol) in THF (2 mL) at room temperature under argon atmo-
sphere. After 5 min, water (3 mL) was added and layers were sep-
arated. Aqueous layer was extracted with EtOAc (3ꢁ3 mL).
Combined organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo. The crude product was purified by column
chromatography (EtOAc/hexane¼1/1). Product (80 mg, 68%); Iso-
mer 1; 1H NMR (300 MHz, CDCl3) 7.30e7.21 (m, 2H), 7.07e7.04 (m,
1H), 6.19 (s, 1H), 5.56e5.55 (d, J¼2.3 Hz, 1H), 5.44 (s, 1H), 4.69e4.67
(m, 1H), 4.08e3.99 (m, 4H), 2.26e2.25 (d, J¼3.7 Hz, 6H), 1.26e1.09
(m, 6H); Isomer 2;; 1H NMR (300 MHz, CDCl3) 7.30e7.21 (m, 2H),
7.07e7.04 (m, 1H), 6.14 (s, 1H), 5.49e5.48 (d, J¼2.3 Hz, 1H), 5.40 (s,
1H), 4.69e4.67 (m, 1H), 4.08e3.99 (m, 4H), 2.26e2.25 (d, J¼3.7 Hz,
6H), 1.26e1.09 (m, 6H). High resolution mass (ESI): calculated for
C25H29Cl2NO9 [MþNa]þ: 580.1117, found: 580.1137.
4.1.9. (S)-3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (8) from compound 3. 0.3 M
KOH solution (0.305 mL, 0.0909 mmol) was added to a stirred so-
lution of (4R)-3-ethyl 5-((2R)-1-(phenylsulfonyl)-3-(tetrahydro-
2H-pyran-2-yloxy)propan-2-yl) 4-(2,3-dichlorophenyl)-2,6-dime-
thyl-1,4-dihydropyridine-3,5-dicarboxylate (53 mg, 0.0909 mmol)
in anhydrous MeOH (1 mL) at room temperature under argon at-
mosphere. After 1 h, solvent was removed. MeI (0.012 mL,
0.1818 mmol) was added to a stirred solution of crude mixture in
DMF (1 mL) at room temperature under argon atmosphere. After
1 h, mixture was diluted with EtOAc (2 mL) and water (2 mL) was
added. Aqueous layer was extracted with EtOAc (3ꢁ3 mL). Com-
bined organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by column
chromatography (EtOAc/hexane¼1/2). (S)-Felodipine (32 mg, 92%);
1H NMR (300 MHz, CDCl3) 7.37e7.28 (m, 2H), 7.14e7.09 (t, J¼7.9 Hz,
1H), 5.87 (br s, 1H), 5.52 (s, 1H), 4.16e4.09 (q, J¼7.4 Hz, 2H), 3.66 (s,
3H), 2.39e2.35 (d, J¼3.1 Hz, 6H), 1.26e1.21 (t, J¼7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 167.8, 167.3, 148.1, 144.2, 144.21, 132.7, 130.9,
129.6, 128.1, 126.9, 103.8, 103.4, 59.8, 50.8, 38.5, 19.4,19.4,14.2; High
resolution mass (ESI): calculated for C18H19Cl2NO4 [MþNa]þ:
406.0589, found: 406.0583; ½a D24:5
ꢃ5.2 (c 1.0 in CH3OH, 589 nm)
ꢂ
[lit.: ½a 2D4:5
ꢃ7.3 (c 1.0 in CH3OH, 589 nm)].
ꢂ
4.1.10. General procedure for compound 3 and 14b from 13a and
13b. Ethyl 3-aminocrotonate (1.2 equiv) was added to a stirred
solution starting material (1 equiv) in pyridine (1.0 M) and then
refluxed. After 4 h, mixture was cooled to room temperature and
aqueous CuSO4 solution was added and the layers were separated.
Aqueous layer was extracted with EtOAc three times. Combined
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The crude mixture was purified by column chromatography
on silica gel to give dicarboxylate product.
p-Toluenesulfonic acid monohydrate (2 equiv) was added to
a stirred solution of dicarboxylate (1 equiv) in ethanol (0.25 M) at
room temperature under argon atmosphere. After 2 h, water was
added and the layers were separated. Aqueous layer was extracted
with EtOAc three times. Combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude mixture was
purified by column chromatography on silica gel to give the prod-
uct. Compound 14b (65%); Isomer 1; 1H NMR (300 MHz, CDCl3)
7.41e7.39 (d, J¼8.5 Hz, 1H), 7.36e7.34 (d, J¼7.9 Hz, 1H), 7.24e7.16
(m, 7H), 7.02e7.00 (m, 1H), 6.93e6.9 (m, 1H), 6.89e6.85 (m, 1H),
6.48 (s, 1H), 5.29 (s, 1H), 4.82e4.79 (m, 1H), 4.02e3.99 (m, 2H),
3.9e3.85 (m, 2H), 3.81e3.79 (d, J¼5.3 Hz, 1H), 3.7e3.66 (m, 1H),
3.13e3.11 (m, 1H), 2.38e2.37 (d, J¼8.6 Hz, 3H), 2.19e2.17 (d,
J¼7.9 Hz, 3H), 2.12e2.09 (d, J¼7.6 Hz, 3H), 1.15e1.1 (m, 3H); Isomer
2; 7.41e7.39 (d, J¼8.5 Hz, 1H), 7.36e7.34 (d, J¼7.9 Hz, 1H), 7.24e7.16
(m, 7H), 7.02e7.00 (m, 1H), 6.93e6.9 (m, 1H), 6.89e6.85 (m, 1H),
6.36 (s, 1H), 5.0 (s, 1H), 4.74e4.71 (m, 1H), 4.02e3.99 (m, 2H),
3.9e3.85 (m, 2H), 3.81e3.79 (d, J¼5.3 Hz, 1H), 3.6e3.52 (m, 1H),
2.8e2.79 (m, 1H), 2.38e2.37 (d, J¼8.6 Hz, 3H), 2.19e2.17 (d,
J¼7.9 Hz, 3H), 2.12e2.09 (d, J¼7.6 Hz, 3H), 1.15e1.1 (m, 3H); 13C
NMR (100 MHz, CDCl3) 147.6, 147.4, 145.7, 145.6, 143.8, 143.8, 143.6,
139.7, 139.0, 134.9, 134.4, 132.9, 132.7, 130.9, 130.3, 130.3, 129.5,
129.5, 129.1, 128.9, 128.5, 128.3, 128.2, 127.9, 127.7, 126.9, 126.8,
103.7, 103.5, 102.3, 102.0, 72.5, 71.7, 61.5, 60.4, 59.9, 59.8, 49.8, 48.8,
39.0, 38.8, 21.6, 21.0, 20.0, 19.8, 19.4, 14.2, 14.1; High resolution mass
(ESI): calculated for C33H34Cl2N2O7S [MþNa]þ: 695.1361, found:
695.1392.
Acknowledgements
This work was supported by a grant from Ahngook pharma-
ceutical company.
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